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Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury

Title
Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury
Authors
Park E.-M.Cho S.Frys K.Racchumi G.Zhou P.Anrather J.Iadecola C.
Ewha Authors
박은미
SCOPUS Author ID
박은미scopus
Issue Date
2004
Journal Title
Stroke
ISSN
0039-2499JCR Link
Citation
vol. 35, no. 12, pp. 2896 - 2901
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Background and Purpose - Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) contributes to ischemic brain injury. Because PARP upregulates proinflammatory genes, we investigated whether inducible nitric oxide synthase (iNOS), a gene involved in the deleterious effects of postischemic inflammation, participates in the mechanisms by which PARP activation contributes to cerebral ischemic injury. Methods - The middle cerebral artery (MCA) was occluded in mice for 20 minutes using an intravascular filament, and injury volume was measured 72 hours later in Nissl-stained brain sections. mRNA expression was assessed in the postischemic brain by the quantitative "real-time" polymerase chain reaction. Results - The PARP inhibitor PJ34 reduced infarct volume and attenuated postischemic iNOS mRNA upregulation by 72%. To determine whether iNOS contributes to the toxicity of PARP, the iNOS inhibitor aminoguanidine was co-administered with PARP inhibitors. Unexpectedly, co-administration of PARP and iNOS inhibitors, or treatment of iNOS-null mice with PARP inhibitors, abrogated the protective effect afforded by iNOS or PARP inhibition alone. The loss of neuroprotection was associated with upregulation of the inflammatory genes iNOS, intercellular adhesion molecule-1, and gp91 phox. Conclusions - The results suggest that iNOS expression contributes to the deleterious effects exerted by PARP activation in cerebral ischemia. However, iNOS activity is required for the protective effect of PARP inhibition and, conversely, PARP activity must be present for iNOS inhibition to be effective. The findings unveil a previously unrecognized deleterious interaction between iNOS and PARP that is relevant to the development of combination therapies for ischemic stroke.
DOI
10.1161/01.STR.0000147042.53659.6c
Appears in Collections:
의학전문대학원 > 의학과 > Journal papers
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